HDAC8-selective inhibitor PCI-34051 protects against aortic dissection by attenuating ferroptosis of vascular smooth muscle cells

Abstract Aortic dissection (AD) is a fatal emergency which lacks for effective drug therapies. Previous studies demonstrated that histone deacetylase 8 (HDAC8) inhibition provides protective benefits in several cardiovascular diseases, including heart failure, fibrosis and cardiac hypertrophy. However, the role of HDAC8 in AD remains unclear. In the present study, we investigated the function of PCI-34051, a highly selective inhibitor of HDAC8 in human aortic smooth muscle cell (HASMC) ferroptosis and β-aminopropionitrile (BAPN)-induced AD in mice. The results showed that PCI-34051 and HDAC8 knockdown significantly inhibited cystine deprivation (CD)- and imidazole ketone erastin (IKE)-induced HASMC ferroptosis, as evidenced by increase in cell viability, reduction in cell injury/death and lipid peroxidation levels in HASMCs. Transcriptome sequencing analysis revealed that the anti-ferroptosis effect of PCI-34051 was associated with the regulation of activator protein-1 (AP-1). Additionally, co-immunoprecipitation results showed that HDAC8 interacts with c-JUN, a component of AP-1. Overexpression of AP-1 (c-FOS and c-JUN) largely abolished the inhibitory effects of PCI-34051 on HASMC ferroptosis. More importantly, PCI-34051 reduced BAPN-induced AD incidence and aortic rupture mortality in mice by inhibiting HASMC ferroptosis and inflammatory response. Taken together, inhibition of HDAC8 by PCI-34051 may provide a preventive or therapeutic strategy for AD by attenuating HASMC ferroptosis.